Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum

Abstract

CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation.

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

“…Our families exhibited widely variable phenotypes, including mild non-syndromic XLMR and XLMR with nystagmus±dysmorphic facial features. In stark contrast to the severely affected individuals reported by Najm et al, 4 our carrier females were either phenotypically normal or less severely affected compared with the males within their family; three of our families had only mild MR, no affected individual had microcephaly and only one of the three individuals undergoing brain MRI exhibited brain malformations or cerebellar hypoplasia. Similar to the recently reported family, 5 macrocephaly was present in one affected male and relative macrocephaly was seen in two of the affected males from family 74.…”

“…[37][38][39] Thus, the anatomical localisation of neural integrator dysfunction provides a plausible explanation for the ocular signs (nystagmus±other ocular deficits, including retinal anomalies and strabismus) occurring in patients with CASK mutations. [2][3][4] Nystagmus does not seem to be related to cerebellar dysfunction, as the majority of patients reported by Najm et al 4 had cerebellar hypoplasia, yet none had nystagmus, and of our three individuals with nystagmus who had MRI brain scans, only one (II-2, family V) had mild cerebellar hypoplasia. Moreover, there was no obvious clinical cerebellar dysfunction in the majority of individuals with nystagmus.…”

“…[1][2][3] Najm et al 4 reported heterozygous inactivating mutations of CASK as causing microcephaly, brainstem and cerebellar hypoplasia, and severe mental retardation (MR) in four females, and a partly penetrant splice mutation causing a severe cerebral malformation in one male who died at the age of 2 weeks. More recently, Piluso et al 5 reported a missense mutation in CASK causing an X-linked syndrome with some features that overlap the FG phenotype.…”

Mutation of plasma membrane Ca 2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca 2+ homeostasis

“…1). More than a dozen X-linked gene defects generate a cerebellar phenotype (36), with those associated with mutations in the synaptic proteins oligophrenin-1 (OPHN1) (37,38) and calcium/calmodulin-dependent serin protein kinase (CASK) (39,40) being well-characterized. The CASK syndrome is caused by the disruption of the gene for the Ca 2+ -CaM-dependent protein kinase, and it may be significant that CASK interacts through its PDZ [Post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and Zonula occludens-1 protein (zo-1)]-binding domain with the C terminal of the PMCA pump (41).…”

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

“…Similarly, the dysfunction of CASK gene, which encodes the calcium/calmodulin-dependent serine protein kinase (MAGUK family), is associated with ataxia, mental retardation and microcephaly. 2 The cerebellar dysfunctions are also linked to ion exchange abnormalities. In one familial case, the cause of the disease was a Ca 2+ imbalance as a result of mutation in the ATP2B3 gene, an ATPase transmembrane transporter that moves Ca 2+ ions out of the cell against concentration gradients.…”